Thioredoxin reductase (TR) is a selenium (Se) containing flavoenzyme that catalyzes NADPH-dependent reduction of the redox protein thioredoxin. TR and thioredoxin form the thioredoxin growth signaling system. Se incorporation is essential for TR activity and Se increases TR activity of both cancer cells in vitro and in vivo. The thioredoxin system is over-expressed in a number of human primary tumors and experimental studies have shown that increased thioredoxin expression is associated with malignant transformation, aggressive tumor growth and resistance of tumors to chemotherapy. Redox activity is essential for the biological activity of thioredoxin and TR is the only known enzyme capable of reducing thioredoxin. Thus, a Se-dependent increase in TR activity could regulate the activity of the thioredoxin system. The applicant has shown that Se stimulates the growth of some human tumors in mice. The hypothesis upon which his studies are based is that Se stimulates the growth of some human tumors by acting through TR to regulate the activity of the thioredoxin redox system. Understanding how Se regulates tumor growth could lead to new therapeutic approaches for treating these tumors. TR also offers a novel target for anticancer drug development and the applicant has identified a novel class of potent and specific thioredoxin reductase inhibitors based on organic derivatives of tellurium. He will investigate the mechanism of action of Se in regulating tumor growth and thioredoxin reductases, clone and sequence two new members of the thioredoxin reductase family he has identified and study the action of the organotellurium compounds as inhibitors of thioredoxin reductase and as potential antitumor agents.
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